Novel 5-nitro-furfurylidene-(2) derivatives and process for producing the same



United States Patent ice 3 262 930 NOVEL NITRO EURFURYLIDENE (2) DE-RIVATIVES AND PROCESS FOR PRODUC- INC THE SAME Heinz Her-linger,Cologne-Flittard, Karl-Heinrich Mayer and Siegfried Petersen,Leverkusen, and Marianne Bock, Wuppertal-Sonnborn, Germany, assignors toFarbenfabriken Bayer Aktiengesellschaft, Leverkusen,

Germany, a corporation of Germany No Drawing. Filed Nov. 13, 1963, Ser.No. 323,225

Claims priority, application Germany, Nov. 23, 1962,

F 38,378 4 Claims. (Cl. 260-240) The present invention relates, ingeneral, to organic chemistry, and, more particularly, to certain novel5- nitro-furfurylidene-(l) derivatives and a unique process forproducing the same via the reaction of S-nitro-furfurol-(Z) withl-arninotetra-hydro-l,4-thiazine-4,4-dioxide. Additionally, theinvention involves the use of the novel compounds of the invention asant-helmintics of rather specific and unique activity as explained ingreater detail hereinafter.

In general, the compounds of the invention may be represented by thefollowing structural formula wherein R represents hydrogen, from 1 to 4lower (C C alkyl radicals, from 1 to 2 aralkyl radicals such as benzyl,or aryl radicals such as phenyl.

Preferably, the indicated reaction of thel-aminotetrahydro-1,4-thiaZine-dioxide with S-ni-tro-furfurol iseffected within an organic solvent medium in which both of the startingcomponents are soluble, and in which the desired end-product isinsoluble.

By reference to United States Patent No. 3,001,992 issued to Bellamy etal. on September 26, 1961, there are described certain5-nitro-furfurylidene (2)-amino compounds carrying heterocyclicsubstituents, but these compounds exhibit only trace-activity againsttrypanosomes, or none at all, and are moreover, extremely toxic.Comparative testing of the unique compounds of the invention withrespect to both their effectiveness and tox- 3,2629% Patented July 26,1966 use of the compounds of the invention over known derivatives ofsomewhat similar chemical structure and similar direction of activity.

Thus, the compounds of the invention are distinguished by a low order oftoxicity and high activity against Trypanosoma cruzi, the causativeagent for the Chagas disease as well as other protozoa, e.g.,Trypanosoma congolense and Trypanosoma bruceiaus. In the formerconnection, for indications against the Chagas disease (the SouthAmerican form of trypanosomiasis, for example, the semicarbazide of5-nitro furfurol-(2) has been used hereto-fore.

In connection with the aforementioned comparative studies, the compoundsof the invention were investigated with white mice. The animals wereinjected with Trypanosoma crwzi, and thereafter treated subcutaneouslywith the unit dosages indicated in Table I on four successive days,commencing one day after initial injection. For evaluation purposes,blood samples of the treated animals were examined microscopically forTrypanosoma cruzi at intervals of one day, commencing the sixth dayafter initial injection, and compared with untreated injected controlanimals of the same species.

As represented by the tabulated results, if the animals are treated withan insufficient dosage of the anthelmintics of the invention, the samenumber of trypanosomes are found in the blood as in that of the controlanimals designates no effect). If, on the other hand, effective doses ofthe preparation are administered to the animals, the blood is free oftrypanosomes for a few days or even for weeks. With reference to TableI, the ultimate test result is indicated by the designation HE (healingefiect), provided the Trypanosoma cruzi cannot be detected within theperipheral blood of the test animals for four weeks or longer, and are-infection takes a positive course. The designation RE (recidivationefiect) indicates a recurrence of trypanosomes in the blood of thetreated animals following a temporary negative microscopic examinationof more than two days. The designation T (traces of effect) indicates aninfluence on the infection which could still be detected. The results ofthe tabulated studies were confirmed on additional strains ofTrypanosoma cruzi of various icity readily demonstrates the advanceachieved through 4.5 origin.

TABLE I Activity against Trypanosoma cruzi (mg/kg.) Toxicity 1 (mg/kg.)(subcutaneously) (subcutaneously) 3 Compound (MN-K J-(]H=NR E RE RE RE-T2 3/3 1/3 0/3 R: NHGO-NH2 N S02 E HE RE RE RE 4) 3/3 0/3 0/3 0/3 -N O 'lT 3/3 2/3 0/3 -N S0 HE RE RE RE 0/3 0/3 0/3 -N S0 HE RE RE RE 5 0/3 0/30/3 HE: Healing elicct.

RE: Recidivation effect. '1: Traces of effect.

No effect.

1 With a single treatment.

2 Number of animals destroyed to total number of animals used. 3 Fourtreatments.

4 Toxic dose; four subcutaneous applications on successive days.

It is believed that the invention may be best understood by reference tothe following specific examples illustrating the application of theforegoing principles and procedures in the production of typicalcompounds of the invention:

Example I Fifteen (15) grams ofl-amino-tetrahydro-l,4-thiazine-4,4-dioxide were treated Within 150milliliters of acetic acid with 14.1 grams of S-nitro-furfurol-(Z), andthe mixture heated for a short time. Orange-red crystals of1-(5-nitro-furfurylidene-amino)-1,4tetrahydrothiazine- 4,4-dioxideseparated out at once which, following filtration via suction andwashing with Water, were immediately found to be analytically pure. Themelting point, following recrystallization from acetic acid, was foundto be 191 C.

Analysis.(C H N O S): Molecular weight, 273. Calculated: C, 39.6%; H,4.03%; N, 15.4%. Found: C, 39.6%; H, 4.25%; N, 15.4%.

Example II 1 amino Z-methyI-tetrahydro-1,4-hydroxythiazine-4,4- dioxide,in amount of 15.4 grams, was dissolved in 100 milliliters of alcohol and5 milliliters of acetic acid, and then added to a solution consisting of14.1 grams of 5- nitro-furfurol-(2) within 100 milliliters of alcohol.The

resultant mixture was heated for a brief period of time and then cooledfor crystallization. Twenty-eight (28) grams of orange-red crystals of1-(5-nitrofurfurylideneamino)-tetrahydro-2-methyl-1,4-thiazine-4,4-dioxideseparated out of the reaction mixture. The melting point, followingrecrystallization from dilute acetic acid, was found to be 172 C.

Analysis.(C H N O S): Molecular weight, 287. Calculated: C, 41.8%; H,4.53%; N, 14.7%. Found: C, 41.92%; H, 4.66%; N, 14.9%.

The production of the 1-amino-2-methyl-tetrahydro- 1,4hydroxythiazine-dioxide used as the starting compound in the foregoingsynthesis can be eflfected by (a) reacting Z-mercaptoethanol withpropylene oxide in the presence of potassium hydroxide.2-hydroxyethyl-Z-hydroxypropyl sulphide of boiling point 160 C. at 15mm. Hg is thus obtained; (b) distillation of 2-hydroxyethyl-2-hydroxypropyl sulphide over p-toluene-sulphonic acid or potassiumhydrogen sulphate under normal pressure. 2- methyl-1,4-hydroxythiane isthus obtained (boiling point: -46" C. at 18 mm. Hg; n =l.4942); (c)oxidation of Z-methyl-l,4hydroxythiane with hydrogen peroxide in aceticacid to form 2-methyl-1,4-tetrahydro-thi0xane-4,4- dioxide (meltingpoint 82 C. following recrystallization from alcohol/ether).

Analysis.-(C H O S): Molecular weight, 150. Calculated: S, 21.3%. Found:S, 21.8%; or (d) reacting 2-methyl-1,4-tetrahydro-thioxane-4,4-dioxidewith hydrazine at C. with the use of an excess of hydrazine, leading to1-amino-2-methyl-1,4-tetrahydro-thiazine-4,4- dioxide (melting point=l15C.).

Analysis.-(C H N O S): Molecular weight, 164. Calculated: C, 36.6%; H,7.32%; N, 17.1%. Found: C, 36.4%; H, 7.31%; N, 16.9%.

Example Ill The 1 amino Z-ethyI-tetrahydro-1,4-thiazine-4,4-dioxide usedas the starting compound in the foregoing synthesis may be obtained in amanner analogous to that described above in connection with Example II,(a)-(d), namely:

(a) 2 hydroxyethyl 2 hydroxybutyl sulphide (boiling point: 164-165 c. at18 mm. Hg; n =l.5058);

(b) 2-ethyl-thioxane-(4,l) (boiling point: 55-60 C. at

17 mm. Hg; n =1.4968), and

(c) 2-ethyl-thioxane-(4,1)-dioxide-(4,4) (melting point:

What is claimed is: 1. A compound of the formula:

wherein R is a member selected from the group consisting of hydrogen,lower alkyl, benzyl and phenyl.

2. The chemical compound,1-(S-nitro-furfurylideneamino)-1,4-tetrahydrothiazine4,4-dioxide.

3. The chemical compound,I-(S-nitro-furfurylideneamino)-tetrahydro-2-methyl-1,4-thiazine-4,4-dioxide.

4. The chemical compound, l-(S-nitro-furfurylideneamino)-tetrahydro-2-ethyl-1,4-thiazine-4,4-dioxide.

References Cited by the Examiner UNITED STATES PATENTS 6/1961 Bellamy eta1. 260-240 WALTER A. MODANCE, Primary Examiner.

I. D. RANDOLPH, Assistant Examiner.

1. A COMPOUND OF THE FORMULA: